| Title: |
Lipid-induced S-palmitoylation of Insulin-Responsive Aminopeptidase (IRAP) drives the onset of insulin resistance in the heart |
| Authors: |
Schianchi, F; Guns, J; Bouwman, FG; Bogie, JF; Nabben, M; Strzelecka, A; van Leeuwen, R; Kapsokalyvas, D; Dennis, KM; Heather, LC; Wang, S; Glatz, JF; Neumann, D; Luiken, JJ |
| Publisher Information: |
Springer |
| Publication Year: |
2026 |
| Collection: |
Oxford University Research Archive (ORA) |
| Description: |
Excessive accumulation of long-chain fatty acids (LCFAs) in cardiomyocytes leads to cardiac lipid-induced insulin resistance (CLIR), impairing insulin signaling and glucose uptake. This metabolic disruption marks a prediabetic state in which cardiomyocytes rely predominantly on lipids for energy provision, leading to lipotoxicity and reduced contractile function over time. Palmitate, the most common dietary LCFA, also serves as a substrate for protein S-palmitoylation, a reversible lipid-based post-translational modification (PTM) that governs protein localization and trafficking through distinct palmitoyl acyltransferase (PATs) isoforms, also denominated as DHHC. In this study, we demonstrate that pharmacological inhibition of protein S-palmitoylation with 2-bromopalmitate (2BP) prevents contractile dysfunction and CLIR in palmitate-overloaded cardiomyocytes. Analysis of the cardiomyocyte palmitoylome disclosed, among other proteins, the insulin-regulated aminopeptidase (IRAP). IRAP translocates together with glucose transporter GLUT4 to the plasma membrane in response to insulin. LCFA-induced hyper-S-palmitoylation of IRAP, mediated by DHHC5, disrupts glucose uptake. Knockdown of DHHC5 or transduction with S-palmitoylation-deficient IRAP rescues both cardiomyocyte glucose uptake and contractile function. These findings identify protein S-palmitoylation, particularly IRAP hyper-S-palmitoylation, as a novel driver of CLIR and associated myocardial dysfunction. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1007/s00018-026-06179-0 |
| Availability: |
https://doi.org/10.1007/s00018-026-06179-0; https://ora.ox.ac.uk/objects/uuid:0161b513-4439-40cd-a342-b524f05628e0 |
| Rights: |
info:eu-repo/semantics/openAccess ; CC Attribution (CC BY) |
| Accession Number: |
edsbas.3AF3F433 |
| Database: |
BASE |